The present invention relates to the use of a type V cyclic nucleotide phosphodiesterase inhibitor for the preparation of a medicament for the treatment of cystic fibrosis. In particular, it relates to the use of specific inhibitors for the preparation of a medicament for the treatment of cystic fibrosis.
Cystic fibrosis (CF) is an autosomal recessive disease characterised by disturbances in ion transport and viscous epithelial mucous secretions. The CF gene protein, CFTR acts as a Cl-channel and is also a key regulator of protein secretion.
CF is caused by mutations in the CF gene, which includes the cystic fibrosis transmembrane conductance regulator protein (CFTR).
WO-A-98/19679 discloses the use of 8-cyclopentyl theophylline (CPT) for the preparation of medicaments for the treatment of cystic fibrosis.
It has now been found that a type V cyclic nucleotide phosphodiesterase (PDE) inhibitor corrects the defective mucin secretory response to the xcex2-agonist isoproterenol in CFTR antibody inhibited submandibular acini. Thus, a type V PDE inhibitor corrects defective CFTR function leading to rational drug treatment for cystic fibrosis.
A type V PDE inhibitor is as effective as IBMX or cpt-cyclic AMP. However, in contrast to IBMX and a selective type IV PDE inhibitor, the type V inhibitor has no effect on cyclic AMP levels and does not stimulate wild type mucin secretion. The data show that correction does not correlate with increase in cyclic nucleotide levels.
According to a first aspect of the present invention, there is provided the use of a type V cyclic nucleotide phosphodiesterase inhibitor in the preparation of a medicament for the treatment of cystic fibrosis.
Suitable type V cyclic nucleotide PDE inhibitors for use in the invention include those described in EP 347146, EP 351058, EP 352960 and in J. Med. Chem., 1993, 36(10), 1387-92.
The type V cyclic nucleotide PDE inhibitor is preferably a selective type V cyclic nucleotide PDE inhibitor.
Compounds can be identified as type V cyclic nucleotide PDE inhibitors using methods known to those skilled in the art, for example as described in EP 293063.
According to a second aspect of the present invention, there is provided the use of a compound of formula (I), 
wherein A is a five- or six-membered ring containing one or more N atoms, X is a substituent of formula (II), 
wherein R1 represents C1-4 alkyl, and X is positioned at either or both of the 2-position and/or the 8-position in (I), in the preparation of a medicament for the treatment of cystic fibrosis.
Preferably, ring A in the compound of formula (I) is of the formula: 
wherein * denotes the points of attachment of the ring, more preferably ring A is of the formula: 
Alternatively, ring A may be of the formula: 
wherein R2 represents hydrogen or C1-4 alkyl and * denotes the points of attachment of the ring.
Alternatively, ring A may be of the formula: 
wherein * denotes the points of attachment of the ring.
In particular, the substituent X is preferably only positioned at the 2-position, i.e. on the 4-pyrimidone ring, in the compounds of formula (I).
According to a further aspect of the present invention, there is provided the use of a compound of formula (III): 
wherein A is a five- or six-membered ring containing one or more N atoms, X is a substituent of formula (II): 
wherein R1 represents C1-4 alkyl, and X is positioned at either or both of the 2-position and/or the 8-position, in the preparation of a medicament for the treatment of cystic fibrosis.
Preferably, ring A of compound (III) has the following formula: 
wherein * denotes the points of attachment of the ring.
In particular, the substituent X is preferably only positioned at the 8-position, i.e. on ring A, in the compounds of formula (III).
The compounds of formulae (I) and (III) may be prepared as described in EP 347146, EP 351058, EP 352960 and J. Med. Chem., 1993, 36(10), 1387-92.
In order to use type V cyclic nucleotide PDE inhibitors in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
The type V cyclic nucleotide PDE inhibitors may be presented in a form suitable for oral administration in a pharmaceutical vehicle convenient for that administrative route. Thus, for example, the medicament may be presented as tablets, capsules, ingestible liquid or a powder preparation. Such formulations can include pharmaceutically acceptable carriers known to those skilled in the art. Formulations suitable for oral administration further include lozenges, pastilles, aerosols and mouthwashes. The type V cyclic nucleotide PDE inhibitors may also be administered by inhalation, that is by intranasal and oral inhalation administration. Formulations suitable for inhalation include powders where the carrier is a solid, and where the carrier is a liquid, the formulation can be administered as a nasal spray or aerosol, or as drops for example.
In yet another altemative, the type V cyclic nucleotide PDE inhibitors may be presented in a formulation suitable for parenteral intravenous administration, such as aqueous or non-aqueous sterile injectable solutions. Such solutions may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Alternatively, the formulation for parenteral administration may be presented as an aqueous or non-aqueous sterile suspension which may include suspending agents and thickening agents.
It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of the inhibitors will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the inhibitors given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
According to a further aspect of the present invention, there is provided a method of treating cystic fibrosis comprising administering a type V cyclic nucleotide phosphodiesterase inhibitor to a patient in need thereof. The type V cyclic nucleotide PDE inhibitor may be a compound of formula (I) or formula (III) as mentioned above.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.